[Inhibitory effects of OKY-046.HCl, a selective thromboxane (TX) A2 synthetase inhibitor, on platelet activating factor (PAF)-induced airway hyperresponsiveness in guinea pigs].
We studied the inhibitory effects of OKY-046.HCl on PAF-induced airway hyperresponsiveness (AHR) in guinea pigs. 1) Inhalation of PAF (1 or 10 micrograms/ml) caused AHR to acetylcholine (ACh) aerosol and increased TXB2 generation in broncho-alveolar lavage fluid (BALF) at 30 min and 60 min, but the AHR and the TXB2 generation disappeared at 2 hr. OKY-046.HCl (100 mg/kg, intraduodenally) inhibited the AHR, which was accompanied by its inhibition of the TXB2 generation. However, no changes of 6-keto-PGF1 alpha in BALF were found. 2) There were no changes in the number of leukocytes; the activities of alkaline phosphatase, N-acetyl-beta-D-glucosaminidase, and lactate dehydrogenase; and the LTC4/D4/E4 in BALF. 3) In bronchus-lung preparations, PAF (1 microgram/min) also caused the AHR and increased TXB2 generation. OKY-046.HCl (100 micrograms/min) inhibited the AHR and TXB2 generation. 4) PAF (1 microgram/ml) evoked TXB2 generation in BALF from normal guinea pigs. OKY-046.HCl (10(-4)M) inhibited its increase. 5) Stable TXA2 (STA2, 1 ng/ml) inhalation also caused AHR to ACh at 30 min. STA2 (0.45 ng/min) also caused the AHR in bronchus-lung preparations. These results suggest that OKY-046.HCl can inhibit PAF-induced AHR by suppressing the generation of TXA2. We also supposed that TXA2 is released from lung parenchyma, airway epithelium and cell components in BALF.
Takehana
Y
Y
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., Matsumoto, Japan.
Hamano
S
S
Kikuchi
S
S
Kusama
H
H
Komatsu
H
H
Okegawa
T
T
Ikeda
S
S
D000179:Acrylates / Q000494:pharmacology*; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000378:metabolism; D004195:Disease Models, Animal; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008689:Methacrylates / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D013928:Thromboxane A2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000179:Acrylates; D008689:Methacrylates; D010972:Platelet Activating Factor; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; C034364:ozagrel